EXPRESSION OF THE EARLY GROWTH RESPONSE-1 AND RESPONSE-2 ZINC FINGER GENES DURING INDUCTION OF MONOCYTIC DIFFERENTIATION

Members of the early growth response (EGR) gene family are rapidly induced after mitogenic stimulation of diverse cell types. The present work has examined EGR gene expression during differentiation of myeloid leukemia cells along the monocytic lineage and in activated monocytes. Low levels of EGR-1 transcripts were detectable in untreated U-937 and HL-60 leukemia cells. In contrast, treatment of these cells with 12-0-tetradecanoylphorbol-13-acetate (TPA) was associated with increases (within 1 h) in EGR-1 mRNA levels. The induction of monocytic differentiation by TPA and other agents was further associated with increases in EGR-2, but not EGR-3 or EGR-4, mRNA levels in these cells. Treatment of resting peripheral blood monocytes with the macrophage colony-stimulating factor (M-CSF) was also associated with rapid (within 15 min) increases in expression of the EGR-1 and EGR-2 genes. The results of nuclear run-on assays demonstrate that EGR-1 mRNA levels are increased in part by transcriptional activation of this gene in M-CSF-stimulated monocytes. The results also demonstrate that both EGR-1 and EGR-2 mRNA levels are regulated at the posttranscriptional level by a labile protein that destabilizes these transcripts. Finally, we demonstrate that dexamethasone, an inhibitor of monocytic differentiation, blocks the associated increases in EGR-1 and EGR-2 expression. Taken together, the results indicate that the EGR-1 and EGR-2 early response genes are involved in the induction of myeloid leukemia cell differentiation along the monocytic lineage and in the activation of human monocytes.